Franco Lori reported on immune responses during treatment interruption of 8 weeks for a group of individuals on HAART vs a group receiving ddI+hydroxyurea. Lori contends that hydroxyurea stimulates an immune response that can control HIV. Previously he has shown data suggesting that hydroxyurea+ddI can produce an HIV specific CD4 immune response. At the '99 Retrovirus Conference Lori reported on using hydroxyurea regimens in acute and chronic infection, and that in both cases he could detect "vigorous" T-helper responses. He treated 10 treatment naÔve patients within 1.7 months of infection with hydroxyurea, ddI and a protease inhibitor. Their average baseline HIV-RNA was 551,000 copies/ml. He reported HIV-RNA was <50 in all patients and the percent of naÔve CD4 and CD8 T-cells were higher than in untreated patients (p=0.0001), and similar to uninfected individuals used as controls for the study. He reported "vigorous" T-helper responses were found in 7/8 patients. Additionally, Lori said HIV was found in quiescent T-cells at an unprecedented low rate (0.3/106). He also reported on 12 individuals with chronic infection with an average baseline HIV-RNA of 51,795 copies/ml. They were treated for 122 weeks with hydroxyurea+ddI. Virus progressively and slowly decreased to an average of 1847 copies/ml at week 40 and 254 copies/ml at week 122, and no viral load rebound was reported. Lori said CD4 cells were able to mediate vigorous HIV-specific T-helper response in 6/12 and the percent of naÔve CD4 and CD8 lymphocytes normalized.

As you may know, the use of hydroxyurea has been scrutinized because in a recent study toxicity and a few deaths occurred. In ACTG 5025 a daily dose of 1200 mg of hydroxyurea was used with ddI and there were two deaths due to pancreatitis. As well, there were discontinuations due to related side effects. It is uncertain as to why the toxicities occurred but it is being analyxed. Higher dosing than generally used of hydroxyurea was used in 5025. It is thought that the higher hydroxyurea dosing may potentiate ddI toxicity. Lower dosing is now being studied. And further analysis of 5025 is ongoing. Bristol Myers said they are scrutinizing that study towards understanding the cause for the toxicities. At the Retrovirus Conference, Diane Havlir, MD from UCSD, discussed this study and encouraged hydroxyurea research to continue.

Franco Lori is currently conducting a study of 225 individuals exploring three daily dose regimens used once, twice and three times daily. 600 mg hydroxyurea will be dose once daily, and 200mg three times per day as well as 300 mg twice daily. 1200 mg will be dosed once daily, 600 mg twice daily and 400 mg three times daily. And, the third once daily dose is 800 or 900 mg, with 300 mg dosed three times daily and 400 mg dosed twice daily.

If a person is using hydroxyurea close monitoring is advised. Labs such as amylase and lipase should be monitored very closely for anyone taking ddI with or without hydroxyurea. As well the patient should be informed of signs and symptoms to look for. Warning signs to watch for are-- stomach pain, nausea, and vomiting. The patient should be told to call their doctor immediately if they notice symptoms.

In this study reported at Retrovirus 2000, the two groups were matched before treatment interruption: length of previous treatment (>2 years in both groups), CD4 count (HAARTs=549±175, PANDAs=495±127), and CD8 count (HAARTs=874±203, PANDAs=805±335). Viremia before interruption, however, was significantly different between HAART patients (<50 copies/ml in 7/8 subjects) and PANDAs (<50 copies/ml in 1/9 subjects). Failure after treatment interruption was defined as viremia rebound >10,000 copies/ml or CD4 count decrease to <200 cells.

Lori reported 5/8 HAART patients failed by week 6 and had to restart therapy, whereas no PANDA had to restart treatment during the entire 8 weeks follow-up. Average viremia rebounded by week 6 from 97 to 16,863 copies/ml in HAART patients (+2.25 log). In contrast, PANDAs average viremia only changed from 843 to 1,596 copies/ml (+0.27 log). PANDAs CD4 and CD8 count remained stable during treatment interruption, while in HAART patients CD4 count decreased (average -208 cells) and CD8 count increased (average +323 cells). CD4/CD8 ratios also remained stable in the PANDAs (0.7); however, they dropped below 0.3 in the HAART group by week 6. Lori concluded reconstitution of HIV specific cellular immune responses obtained during the treatment of chronically infected patients was associated with the control of viral rebound during treatment interruption.